Breaking News: Expert Perspective on Venclexta (venetoclax) Approval

Published on
April 12, 2016

Topics include:
Treatment

The
U.S. Food and Drug Administration (FDA) has approved a new drug Venclexta
(venetoclax) for use in
CLL patients with the 17p deletion. Andrew Schorr interviewed CLL expert Dr.
Thomas Kipps to get his perspective on what this new approval means for
patients.

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello and welcome to Patient Power. I'm Andrew Schorr. With us is one of our regular guests, a
leading CLL expert, Dr. Thomas Kipps from UC San Diego Moores Cancer
Center. Dr. Kipps, thank you for
joining us. We've just had yet another
drug approved for CLL. Tell us what it
means for patients.

Dr. Kipps:

Well, thank you, Andrew. It's a pleasure to see you again and to join
your program. I think it's a great
program.

We're very excited.
Yes, venetoclax (Venclexta) was just approved for treatment of patients
with chronic lymphocytic leukemia that have the 17p deletion. This is approved for patients who have had
prior therapy and have relapsed after therapy.
So it's a somewhat narrower indication, but we think it's actually a
first step towards perhaps a larger indication for use of this drug.

We've been fortunate to be involved in work on this drug
since the very beginning, and we're involved in the first clinical trials with
venetoclax here in this country, actually an international effort with
Australia involved. And the drug at
first impressed me as being a very potent one.
It attacks a very fundamental mechanism that contributes to the
leukemia's survival. And this is why we're very excited about it, because it's
somewhat of a designer drug that goes specifically after a protein, which protects
the leukemia cell from dying and protects the leukemia cell from dying even
with chemotherapy.

What the drug does is it circumvents this protein and makes
the cell susceptible to just undergoing cell death spontaneously, and this can
sometimes result in very dramatic reductions in the leukemia cell counts as
well as reductions in the leukemia tumors that we see in the lymph nodes.

Now, very early on when we were using this drug, we were
impressed by the fact that even though it's a pill that patients can take it
had a lot of very potent activities, and some of the first few patients that we
had in our early Phase I clinical trial were patients treated in Australia who
had very large tumor burdens. And the investigators there were concerned, because
they had indication that the tumor responded so quickly to treatment that you
saw increases in electrolytes that indicated what we were having was a tumor
lysis syndrome. Namely, it's great when
we say tumor lysis to get rid of the tumor, but sometimes too much of a good
thing can be a bad thing.

And when the tumor cells are destroying themselves so
quickly, they release the internal contents of the leukemia cell into the
bloodstream. And that results in electrolyte imbalances, some of which can have
some very deleterious consequences. The
most notable, of course, is that when you have an increase in, say, an
electrolyte called potassium, that can interfere with conductivity of the
heart, and we know that that's very important.
We want our heart to continue beating.

And so we actually scaled back the dosage that we started
out with. We started out with a dose
that we thought was going to be the right one, and we had to come way down and
start with lower doses and only gradually escalate to higher doses. And we were actually very impressed with the
activity of this drug. It was a drug
that was developed after another drug that we had also been testing in the
clinic called navitoclax, and unlike navitoclax this drug seemed to be specific
for the leukemia.

The earlier drugs seemed to also affect the platelet count
in a way that was difficult to handle, because the platelet counts would go
down, so we had a problem with going up with the dosage of the drug. Now, with venetoclax we did not have that
problem, but we still were concerned about this problem of tumor lysis. It was unfortunate, this trial opened up in
more sites across the United States and abroad.
There were two patients almost within one week of one another, happened
during the ASH meeting, unfortunately, one patient on the East Coast, one
patient in the Northwest that were treated with this drug, and these patients
had very large tumors. One patient had a
tumor the size of large grapefruits and maybe a small basketball, if you
will.

And the tumor melted away so quickly, and it was not fully
appreciated how dramatic this response was, and these patients succumbed to
tumor lysis. Namely, the potassium level
got so high that the heart lost the ability to contract, and that's not
something that's compatible with living.
This is something I tell patients, that the tumor lysis syndrome really
has two symptoms until your heart stops. And that's a hard thing, so we have to
be extremely careful with this drug.

And we then adopted strategies to dose down, way down, and
actually do something very extreme, namely, to take patients and bring them
into the hospital and to watch over them like a hawk. We watched over their electrolytes. We watched over their cell counts and other
factors. And if they had any indication of having this tumor lysism we jumped
on it immediately, and we treated it medically.
I'm happy to say that we haven't lost any patients since on this drug,
we've not lost any patients here at UC San Diego. And we've not had to even
resort to such measures as what's called hemodialysis, which is the measure
that you can use. If the electrolytes go
up and up and you can't keep it down with medicines, then you can have dialysis
to lower the concentration of the electrolytes.

I think it's been very well tolerated, and in fact most
patients when they take the pill they don't experience any symptoms whatsoever,
and they feel fine. I have had some
patients refuse to get out of their street clothes when they're in the
hospital. They say, well, I'm not sick,
and that's the way it usually has been.
But still, the caution has been important.

Now, we have been able to recognize, of course, that the
more tumors you have the greater the risk of tumor lysis syndrome, and so what
we've done is to stratify patients into risk categories. Those patients that have high tumor burden
are stratified into receiving the drug in a very close setting in the hospital,
and those patients with low tumor burden who do not have the risk for tumor
lysis can be then started to be treated as an outpatient.

And as we learn more about when this tumor lysis occurs and
how to avoid it and what measures to take when we start seeing the earliest
indications of it, it's become easier to administer this drug as an
outpatient. And we're very excited that
this drug is finally approved.

You can imagine when we had patients on this protocol that I
mentioned to you that died, no one wants to see this, but it was the dramatic
effects that we had with this drug that really made the FDA say that, hey, wait
a minute, there's some very important activity with this drug, and we should
pursue further studies. And I think if
we can manage this drug safely, it is extremely powerful.

It's powerful in patients who really are refractory to
chemotherapy in the conventional sense, because what it does is it bypasses
what the chemotherapy does. The
chemotherapy oftentimes works through a protein which we call p53. This protein is lost in many patients who
have the deletion 17p, and what this means is that the p53 is absent or
dysfunctional, and it cannot induce the proteins inside the cell that act like
this drug. So this drug kind of bypasses
the need for p53 and allows for the tumor to actually undergo this cell death
process in a way that chemotherapy can only hope for and can't do when p53 is
lacking.

And for that reason, its indication now has been approved
for patients who have the deletion in 17p.
Those patients I would not give conventional chemotherapy to because the
cells, the leukemia cells, are resistant to the drug, and the chemotherapy can
affect other cells in the body such as the bone marrow.

I think this drug is important from the standpoint it has
activity, but it's also been the only drug that I've seen that of all the new
drugs that we've had come out to consistently give a fairly high yield, what we
call complete responses, without any evidence of minimal residual disease. And we can check for that in the bone
marrow. When we treat patients, we then
see if they're responding. If their
counts normalize and their lymph nodes disappear, then we can look at the bone
marrow and see if there are any residual cells there.

And we have some very sensitive tools to do this with
sensitive flow cytometry, which can detect one in 10,000 cells, and then we're
now using genetic techniques that can detect one cell in a million. And we've noticed that some of our patients
actually became cleared of their leukemia cells so that we couldn't even detect
the leukemia by these sensitive methods.

Now, it's interesting that one patient I remember had no
evidence of leukemia in the bone marrow but still had some lymph nodes on the
CT scans that we could recognize. And we thought this patient had a complete
response, so we actually biopsied these lymph nodes and found only scar
tissue. So this patient really has no
evidence of detectable leukemia, and I think this is very encouraging because
if we're going to cure this disease, it would seem that we have to eradicate
the leukemia entirely.

About a quarter of patients who take the drug may achieve
this degree of clinical response. We're
seeing higher response rates in patients who are receiving this drug in
combination with antibodies such as rituximab (Rituxan) or obinutuzumab
(Gazyva). I think that's very
encouraging—still not a hundred percent, but still it's a step in the right
direction.

So I think that venetoclax, even though it's approved for
this narrow indication might see a wider use for patients without 17p in the
future, and clinical studies are undergoing right now to try and test that and
to demonstrate the clinical utility of this drug for other types of patients as
well.

Andrew Schorr:

Thank you for stressing the safety. I know that's so important. Patients hear there's a new addition, and
they say, is it for me? So right now,
under the approval, how do patients determine with their doctor whether this is
the right drug for them?

Dr. Kipps:

Okay. The
approval indication is pretty narrow.
Namely, patients must have received some form of prior therapy. So if you've not received prior therapy for
the leukemia, then it's really not an indication for you. Now, if you've received prior therapy and
have relapsed from therapy, then what you can do is to essentially have the
FISH analysis, which you should have in any case. With the FISH analysis, you can tell whether
the leukemia cells have this deletion in the short arm of chromosome 17. That's the deletion 17p. So if you've relapsed after prior therapy and
have the FISH analysis that shows you to have 17p deletion, then you are
eligible to take this drug by the new FDA indication.

Andrew Schorr:

Okay. We
want to thank you for your time, Dr. Kipps. I know you need to get back to clinic, but
this is news for patients, and we'll be following it carefully. And, of course, what you said about
monitoring with a very powerful new addition, this is critical, and having it
be right for the patients with the 17p deletion who have had prior
therapy.

Dr. Tom Kipps from UC San Diego, thank you for being
with us and telling us about a new addition to the CLL armamentarium.

I'm Andrew Schorr.
Remember, knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Related Programs

Dr. William Wierda, medical director of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, joins Patient Power to discuss the approval of Venclexta (venetoclax) for use in CLL patients with the 17p deletion.